High-density lipoprotein (HDL) particles have multiple atheroprotective properties, including removal of excess cholesterol from peripheral tissues, inhibition of vascular inflammation, and reduction of oxidative stress. It is thought that HDL function is mediated by the molecules bound to HDL particles, which include proteins, lipids, and microRNAs. HDL function and composition have been shown to be impaired in various disease states and measures of HDL function are strong, independent predictors of cardiovascular disease risk. Recent work has shown that exercise training improves HDL function in a dose-specific manner. Thus, the overall goal of the proposed study is to examine the effects of exercise dose and type on HDL function and identify the clinical and molecular factors underlying exercise-induced changes in HDL function. The proposed study will utilize existing data and samples from four large, completed NIH-funded clinical exercise trials (N=1224) to test the study hypotheses: HERITAGE Family Study (N=731; 5 mos, same aerobic dose in healthy adults), STRRIDE AT/RT (N=144; 8 mos, aerobic, resistance, or combination training in overweight adults with mild dyslipidemia), STRRIDE-PD (N=175; 6 mos, 4 groups differing in aerobic exercise amount and/or intensity in adults with pre- diabetes), and HART-D study (N=174; 9 mos, time-matched aerobic, resistance, or combination training in diabetics). Specifically, Aim 1 will examine how exercise amount, exercise intensity, and exercise type affect three measures of HDL function (cholesterol efflux capacity, anti-inflammatory and anti-oxidant properties) and whether the exercise effects on HDL function differ by race, sex, and/or metabolic profile (e.g., diabetes, metabolic syndrome, obesity). Aim 2 will examine the effects of exercise training on the HDL proteome, HDL lipidome, and HDL microRNA profiles and validate sex- and race-specific HDL molecular signatures that predict exercise-induced changes in HDL function. Furthermore, Aim 2 will integrate the generated HDL function and HDL composition data with available genomic, metabolomic, and muscle gene expression data to identify novel genes, pathways, and networks associated with exercise-induced changes in HDL function. The proposed research will determine the amount, intensity, and type of exercise that improves HDL function and will identify specific groups of molecules underlying these functional changes. Identifying clinical and molecular predictors of exercise-induced changes in HDL function could help provide targeted exercise programs tailored to specific sex-race-disease groups to maximize the benefits.